1007 In 1938, Turner reported a syndrome of sexual infantilism, short stature, webbed neck, cubitus valgus, and primary amen- orrhea in seven female patients. Later in 1954, it was observed that the ovaries were usually replaced by streaks of stroma with- out follicles; hence the name gonadal agenesis. Negative sex chromatin was discovered in 1954; only one X chromosome was demonstrated cytogenetically in these patients in 1959.
About 99% of 45,X fetuses abort spontaneously and only 1% of these fetuses survive to term. Despite this, Turner syn- drome is a relatively common chromosome disorder affecting 1 in 2500 female live births. About 10% of all spontaneous abor- tuses have a 45,X karyotype.
GENETICS/BASIC DEFECTS
1. Caused by complete or partial X chromosome monosomy in all or some of the body cells
2. Short stature and skeletal manifestations (short 4th metacarpals, cubitus valgus, Madelung deformity, high- arched palate, and short neck) are attributed to haploin- sufficiency of the SHOX, the short-stature homeobox- containing gene on the pseudoautosomal region of the sex chromosomes (Xp22 and Yp11.3). SHOX gene is also known as PHOG gene for pseudoautosomal homeobox- containing osteogenic gene, lying on the very tip of the short arm of both sex chromosomes
3. Pathogenesis
a. Gonadal dysgenesis: Oocytes undergoing accelerated degeneration during the first meiosis, resulting in loss of nearly all oocytes by late childhood
b. Somatic stigmata
i. Lymph fluid stasis caused by lymphatic hypopla- sia results in distension of the main and tributary lymphatic ducts and generalized lymphedema ii. Distended lymphatics and lymphedema cause
mechanical extension of surrounding tissues, giving rise to deformations recognized as lym- phatic obstruction stigmata:
a) Webbed neck
b) Low posterior hairline c) Rotated auricles d) Puffy hands and feet e) Redundant skin
f) Nail hypoplasia
g) Whorl dominant finger tip pattern 4. Phenotype–karyotype correlation
a. Absence or deletion of the short arm of the X chromo- some correlates with Turner stigmata:
i. Short stature ii. Broad chest iii. Widespread nipples
iv. Webbing of the neck
v. Peripheral lymphedema at birth
vi. Short 4th metacarpals vii. Hypoplastic nails viii. Multiple pigmented nevi
ix. Coarctation of the aorta
b. Absence or deletion of the long arm of the X chro- mosome correlates with infertility and gonadal dys- genesis.
c. The degree of mosaicism correlates with the presence of clinical features of Turner syndrome.
d. Severe phenotype associates with a small or tiny ring X chromosome which lacks the XIST (X-inactive- specific transcript) at Xq13:
i. Loss of XIST results in functional X disomy for the sequences contained in the ring.
ii. Some r(X), ascertained because of severe pheno- types, undergo X inactivation.
CLINICAL FEATURES
1. Skeletal manifestations
a. Short stature (100%): an invariant feature in the 45,X Turner syndrome
b. Characteristic growth pattern i. Intrauterine growth retardation
ii. Progressive decline in growth velocity in childhood iii. Lack of pubertal growth spurt
iv. Delayed growth cessation c. Cubitus valgus
d. Madelung deformity of the wrist (a bayonet-like deformity of the wrist) with decreased extension and supination
e. Hypoplastic nails f. Short 4th metacarpals
2. Characteristic craniofacial features
a. Down slanting of the palpebral fissures b. Epicanthal folds
c. Occasional ptosis and strabismus d. Midfacial hypoplasia
e. Broad nasal bridge f. High arched palate g. Micrognathia h. Rotated auricles 3. Teeth
a. Crowding b. Malocclusion 4. Neck
a. Short and broad neck
b. Webbed neck (pterygium coli) with low posterior hairline from the resolution of the cystic hygroma that was present in fetal life
5. Chest
a. Shield chest
b. Increased internipple distance
6. Congenital heart defects (30%) a. Coarctation of the aorta b. Bicuspid aortic valve c. Aortic stenosis
d. Aneurysm (aortic root dilatation) e. Cystic medial necrosis of the aorta 7. Vascular anomalies
a. Multiple intestinal telangiectasia b. Hemangiomas
c. Lymphangiectasia d. Venous ectasias
e. Intermittent and recurrent gastrointestinal bleeding f. Protein-losing enteropathy secondary to gastrointesti-
nal lymphangiomas
g. Chylous fluid accumulation in the abdomen and chest 8. Peripheral lymphedema in the newborn infant involving
dorsum of the hands and feet 9. Nail dysplasia
a. Concave fingernails b. Upturned toenails 10. Skin
a. Redundant skin
b. Multiple pigmented nevi
c. Tendency of hypertrophic scarring or keloid formation 11. Gonadal dysgenesis
a. Sexual infantilism: one of the most common clinical findings
b. Primary amenorrhea (the rule)
c. Spontaneous menstruation occurring in about 5% of patients. Some of these women even give birth (3–5%).
d. Delayed pubertal development in most patients e. Up to 30% of patients with at least some pubertal
development indicating the presence of follicles in their ovaries in adolescence
f. A high frequency of miscarriage reported among the spontaneous pregnancies of women with Turner syndrome
g. Progressive ovarian failure h. Infertility/sterility
12. Genitourinary lesions
a. Horseshoe and ectopic kidneys b. Ureteropelvic obstruction c. A double collecting system d. A bifid renal pelvis e. Hydronephrosis
f. Vaginal agenesis: rare
13. Hypertension (common even without cardiac or renal malformations)
14. Conductive and sensorineural hearing losses 15. Autoimmune disease
a. A markedly increased incidence of thyroid antibodies b. Autoimmune hypothyroidism
c. Impaired serum glucose tolerance in 25–60% of patients
d. Diabetes mellitus in 5% of patients
e. An increased incidence of inflammatory bowel disease i. Regional enteritis
ii. Ulcerative colitis f. Rheumatoid arthritis g. Acute hyperthyroidism: rare
16. Abnormal dermatoglyphics a. Predominant digital whorls b. Distal triradii
17. Psychosocial aspects
a. Significantly higher verbal level than performance level attributed to a specific space form-perception deficit b. Arithmetic subtests: most difficult among verbal sub-
tests
c. Difficulty in performance i. Reading
ii. Figure drawing iii. Geometry
iv. Arithmetic
18. Presence of Y chromosome material in some cases of Turner syndrome
a. A high risk of developing gonadoblastoma and dys- germinoma
b. Requiring preventive removal of the dysgenetic gonads
19. Mosaic patients with a structurally abnormal X chromo- some
a. Classic Turner phenotype
i. X-derived marker in majority of cases
ii. Usually a large ring X chromosome that includes XIST not associated with a severe phenotype, although a low IQ or even mental retardation has been observed in some cases
b. Severe phenotype i. Mental retardation
ii. Dysmorphic features uncharacteristic of Turner syndrome
iii. Observed in patients associated with a small or tiny ring X chromosome lacking the XIST gene at Xq13
DIAGNOSTIC INVESTIGATIONS
1. Endocrine study
a. Very low estrogen levels
b. Elevated pituitary gonadotrophins after puberty 2. Karyotype analyses
a. 45,X
i. Observed in 50% of cases
ii. Maternal origin of the X chromosome in two- thirds of cases
b. Structurally abnormal sex chromosome, such as i(Xq) c. Mosaicism with a second cell line containing a nor-
mal or abnormal X or Y
i. Most common forms of mosaicism a) 45,X/46,XX
b) 45,X/46,X,i(Xq)
ii. Containing a sex marker chromosome in about 20% of cases
a) Sex marker chromosome: usually an X chro- mosome
b) Second cell line containing a structurally abnormal Y chromosome in 6% of cases d. Determination of the chromosomal origin of sex
marker chromosomes
i. Fluorescence in situ hydridization (FISH)
ii. Primed in situ labeling (PRINS) diagnostic for repetitive sequences in specific human chromo- somes
e. Painting probes and libraries to detect “hidden”
mosaicism
i. Classical alpha-satellite probes for the X (CEP-X) chromosome and Y chromosomes (CEP-Y) (Vysis)
ii. Whole chromosome painting probes (WCP-X, WCP-Y) (Vysis)
iii. XIST-digoxigenin (Oncor) hybridizing specifi- cally to Xq13.2 indicating the X-inactivation center
iv. DXZ4-biotin (Oncor) hybridizing specifically to a cluster of 50–100 copies of a 3-kb repeat in the Xq24 region
v. Subchromosomal painting libraries (SCPL116 specific for the short arm of the X chromosome, SCPL102 specific for the long arm of the X chromosome)
3. Identification of specific X and Y sequences
a. Important for establishing phenotype-karyotype cor- relations
b. Important for adequate genetic counseling
c. PCR to identify the presence or absence of specific Y sequences
4. Echocardiography for cardiovascular malformations 5. Renal ultrasound for renal anomalies
6. Radiography
a. Madelung deformity
i. Prominent and dorsally dislocated but reducible distal ulna
ii. Short and bowed radius
iii. Carpal articular surface of the radius tilted in a volar and ulnar direction producing a triangular configuration and premature fusion of the ulnar side of the radial growth plate
b. Short 4th metacarpals and metatarsals c. Short distal phalanges with tufting d. Carpal bone fusion
e. Pes cavus
f. Irregular tibial metaphyses with mushroom projec- tions on the medial surface of the proximal tibial metaphyses
g. Spine
i. Schmorl’s nodes (abnormalities of cartilaginous end plates)
ii. Scheurermann’s disease of the vertebrae (osteo- chondrosis of vertebral epiphyses in juveniles) iii. Scoliosis
iv. Lack of lumbar lordosis v. Congenital hip dislocation h. Skull
i. Midfacial hypoplasia ii. An obtuse cranial base angle iii. Short cranial base
i. Osteoporosis 7. Other investigations
a. Blood pressure measurement for hypertension b. Thyroid function
c. Audiology for conductive and sensorineural hearing loss d. Orthodontic evaluation
e. Orthopedic evaluation f. Glucose intolerance
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib: low
b. Patient’s offspring: rarely pass to offspring due to infertility
2. Prenatal diagnosis
a. Maternal serum screening (α-fetoprotein, hCG, inhibin A, unconjugated estriol)
b. Ultrasonographic screening i. Fetal hydrops
ii. Increased nuchal translucency iii. Fetal cystic hygroma
iv. Coarctation of the aorta v. Left-sided cardiac defects vi. Lymphedema
vii. Renal anomalies
viii. Intrauterine growth retardation ix. Polyhydramnios
x. Oligohydramnios
c. Amniocentesis or CVS for chromosome analysis 3. Management
a. Psychosocial counseling
i. Degree of parental understanding and appropriate attitudes toward the patient with Turner syndrome depends, in general, on good family relationships, socioeconomic level of the family, and appropri- ate physician’s counseling
ii. Short stature: a major concern when entering school
iii. Pubertal failure and sterility: major concerns to the parents and patients at pubertal age
iv. Webbed neck less frequent concern cosmetically unless that defect is marked and visible
v. Occasional parental rejection and over protec- tiveness
vi. Child’s adjustment to the disease influenced by parental personalities and their ability to cope with the implications of the syndrome
vii. Development of a high degree of social compe- tency permitting patients to be integrated into a society where they will be self sufficient and self-sustaining
b. Estrogen replacement therapy
i. To induce near normal pubertal development ii. To prevent osteoporosis
iii. To reduce the risk of developing cardiovascular disease
c. Growth hormone with or without anabolic steroids for short stature
d. Pregnancies among women with Turner syndrome i. A high risk of miscarriages among spontaneous
pregnancies
ii. A high incidence of cardiac abnormalities, even fatal aortic dissection
Matsuo M, Muroya K, Nanao K, et al.: Mother and daughter with 45,X/46,X,r(X) (p22.3q28) and mental retardation: analysis of the X- inactivation patterns. Am J Med Genet 91:267–272, 2000.
Migeon BR, Luo S, Jani M, et al.: The severe phenotype of females with tiny ring X chromosomes is associated with inability of these chromosomes to undergo X inactivation. Am J Hum Genet 55:497–504, 1994.
Migeon BR, Ausems M, Giltay J, et al.: Severe phenotypes associated with inactive ring X chromosomes. Am J Med Genet 93:52–57, 2000.
Nietzel A, Rocchi M, Starke H, et al.: A new multicolor-FISH approach for the characterization of marker chromosomes: centromere-specific multicol- or-FISH (cenM-FISH). Hum Genet 108:199–204, 2001.
Ogata T, Kosho T, Wakui K, et al.: Short stature homeobox-containing gene duplication on the der(X) chromosome in a female with 45,X/46,X, der(X), gonadal dysgenesis, and tall stature. J Clin Endocrinol Metab 85:2927–2930, 2000.
Ogata T, Matsuo N: Turner syndrome and female sex chromosome aberrations:
deduction of the principal factors involved in the development of clinical features. Hum Genet 95:607–629, 1995.
Ogata T, Muroya K, Matsuo N, et al.: Turner syndrome and Xp deletions: clin- ical and molecular studies in 47 patients. J Clin Endocrinol Metab 86:5498–5508, 2001.
Page DC: Y chromosome sequences in Turner’s syndrome and risk of gonadoblastoma or virilisation. Lancet 343:240, 1994.
Pavlidis K, McCauley E, Sybert VP: Psychosocial and sexual functioning in women with Turner syndrome. Clin Genet 47:85–89, 1995.
Pellestor F, Girardet A, Lefort G, et al.: Use of the primed in situ labeled (PRINS) technique for a rapid detection of chromosomes 13, 16, 18, 21, X and Y. Hum Genet 95:12–17, 1995.
Rao E, Weiss B, Fukami M, et al.: Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nature Genet 16:54–63, 1997.
Robinson A: Demography and prevalence of Turner syndrome. In Rosenfeld RG, Grumbach MM (eds): Turner syndrome. New York: Marcell Dekker.
1990, pp 93–100.
Robinson DO, Dalton P, Jacobs PA, et al.: A molecular and FISH analysis of structural abnormal Y chromosomes in patients with Turner syndrome. J Med Genet 36:279–284, 1999.
Saenger P, Wikland KA, Conway GS, et al.: Recommendations for the diagno- sis and management of Turner syndrome. J Clin Endocdrinol Metab 86:3061–3069, 2001.
Schmid W, Naef E, Murset G, et al.: Cytogenetic findings in 89 cases of Turner’s syndrome with abnormal karyotypes. Humangenetik 24:93–104, 1974.
Schwartz RP, Sumner TE: Madelung’s deformity as a presenting sign of Turner’s syndrome. J Pediatr 136:563, 2000.
Schwartz S, Depinet TW, Leana-Cox J, et al.: Sex chromosome markers: char- acterization using fluorescence in situ hybridization and review of the lit- erature. Am J Med Genet 71:1–7, 1997.
Subramaniam PN: Turner’s syndrome and cardiovascular anomalies: a case report and review of the literature. Am J Med Sci 297:260–262, 1989.
Sybert VP: Turner syndrome. In: Cassidy SB, Allanson JE (eds):
Management of Genetic Syndromes. 1st ed. New York: Wiley & Sons, 2001:459–484.
Tsezou A, Hadjiathanasiou C, Gourgiotis D, et al.: Molecular genetics of Turner syndrome: correlation with clinical phenotype and response to growth hormone therapy. Clin Genet 56:441–446, 1999.
Turner HH: A syndrome of infantilism, congenital webbed neck and cubitus valgus. Endocrinology 23:566–578, 1938.
Turner C, Dennis NR, Skuser DH, et al.: Seven ring(X) chromosomes lacking the XIST locus, six with an unexpectedly mild phenotype. Hum Genet 106:93–100, 2000.
Van Dyke DL, Wiktor A, palmer Clin Genet, et al.: Ulrich-Turner syndrome with a small ring X chromosome and presence of mental retardation. Am J Med Genet 43:996–1005, 1992.
Wolff DJ, Brown CJ, Schwartz S, et al.: Small marker X chromosomes lack the inactivation center: implications for karyotype/phenotype correlations.
Am J Hum Genet 55:87–95, 1994.
Zinn AR, Page DC, Fisher EMC: Turner syndrome: the case of the missing sex chromosome. Trends Genet 9:90–93, 1993.
REFERENCES
American Academy of Pediatrics. Committee on Genetics. Health supervision for children with Turner syndrome. Pediatrics 96:1166–1173, 1995.
Bercu BB, Kramer SS, Bode HH: A useful radiologic sign for the diagnosis of Turner’s syndrome. Pediatrics 58:737–739, 1976.
Binder G, Schwarze CP, Ranke MB: Identification of short stature caused by SHOX defects and therapeutic effect of recombinant human growth hor- mone. J Clin Endocrinol Metab 85:245–249, 2000.
Cervantes A, Guevara-Yáñez R, López M, et al.: PCR-PRINS-FISH analysis of structurally abnormal sex chromosomes in eight patients with Turner phe- notype. Clin Genet 60:385–392, 2001.
Chen H, Espiritu C, Casquejo C, et al.: Internipple distance in normal children from birth to 14 years and in children with Turner’s, Noonan’s, Down’s, and other aneuploidies. Growth 38:421–436, 1974.
Chen H, Hoffman W, Chang CH, et al.: Lymphocytic thyroiditis, myasthenia gravis, and Turner syndrome. Birth Defects XIV:137–147, 1978.
Chen H, Faigenbaum D, Weiss H: Psychosocial aspects of patients with the Ullrich-Turner syndrome. Am J Med Genet 8:191–203, 1981.
Collins AL, Cockwell AE, Jacobs PA, et al.: A comparison of the clinical and cytogenetic findings in nine patients with a ring(X) cell line and 16 45,X patients. J Med Genet 31:528–533, 1994.
Ellison JW, Wardak Z, Young MF, et al.: PHOG, a candidate gene for involve- ment in the short stature of Turner syndrome. Hum Mol Genet 6:1341–1347, 1997.
Fernández R, Méndez J, Pásaro E: Turner syndrome: a study of chromosomal mosaicism. Hum Genet 98:29–35, 1996.
Fernández-García R, Carcía-Doval S, Costoya S, et al.: Analysis of sex chro- mosome aneuploidy in 41 patients with Turner syndrome: a study of “hid- den” mosaicism. Clin Genet 58:201–208, 2000.
Fingby N, Archibald RM: Skeletal abnormalities associated with gonadal dys- genesis. Am J Radiol 9:354–361, 1965.
Gicquel C, Cabrol S, Schneid H, et al.: Molecular diagnosis of Turner syn- drome. J Med Genet 29:547–551, 1992.
Gøtzsche CO, Krag-Olsen B, Nielsen J, et al.: Prevalence of cardiovascular malformations and association with karyotypes in Turner’s syndrome.
Arch Dis Child 71:433–436, 1994.
Gravholt CH, Huul S, Naeraa RW, et al.: Morbidity in Turner syndrome. J Clin Epidemiol 51:147–158, 1998.
Hall JG, Gilchrist DM: Turner syndrome and its variants. Pediatr Clin North Am 37:1421–1440, 1990.
Hassold T, Benham F, Leppert M: Cytogenetic and molecular analysis of sex- chromosome monosomy. Am J Hum Genet 42:534–541, 1988.
Held KR, Kerber S, Kaminsky E, et al.: Mosaicism in 45,X Turner syndrome:
does survival in early pregnancy depend on the presence of two sex chro- mosomes? Hum Genet 88:288–294, 1992.
Hook EB, Warburton D: The distribution of chromosomal genotypes associat- ed with Turner’s syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism. Hum Genet 64:24–27, 1983.
Hreinsson JG, Otala M, Fridstrom M, et al.: Follicles are found in the ovaries of adolescent girls with Turner’s syndrome. J Clin Endocrinol Metab 87:3618–3623, 2002.
Hunter AG, DesLauriers GE, Gillieson MS, et al.: Prenatal diagnosis of Turner’s syndrome by ultrasonography. Can Med Assoc J 127:401, 1982.
Jacobs P, Dalton P, James R, et al.: Turner syndrome: a cytogenetic and molec- ular study. Ann Hum Genet 61:471–483, 1997.
Kleczkowska A, Dmoch E, Kubien E, et al.: Cytogenetic findings in a consec- utive series of 478 patients with Turner syndrome. The Leuven experi- ence 1965–1989. Genet Couns 1:227–233, 1990.
Kosho T, Muroya K, Nagai T, et al.: Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the develop- ment of Turner syndrome. J Clin Endocrinol Metab 84:4613–4621, 1999.
Larsen T, Gravhott CH, Tillebeck A, et al.: Parental origin of the X chromo- some, X chromosome mosaicism and screening for “hidden” Y chromo- some in 45,X Turner syndrome ascertained cytogenetically. Clin Genet 48:6–11, 1995.
Lesczynki S, Kosowica J: Radiologic changes in the skeletal system in Turner’s syndrome-Review of 102 cases. Prog Radiol 1:510–517, 1965.
Fig. 1. A multi-septated cystic hygroma is observed in a fetus with Turner syndrome at 18 weeks of gestation.
Fig. 2. A 45,X fetus showing massive cystic hygroma and hydrops fetalis.
Fig. 3. A newborn with 45,X showing classic facial features, webbed neck, shield chest, and wide space between nipples.
Fig. 4. A 45,X newborn with classic facial features (epicanthal folds, down-slanting palpebral fissures, flat nasal bridge, receding chin, low- set/posteriorly rotated ears) and excessive nuchal skin folds.
Fig. 5. Two 45,X newborns with severe lymphedema of the dorsum of hand and feet and toe nail hypoplasia.
Fig. 6. A 45,X girl showing short stature, classic facial features, severe webbed neck, shield-like chest, and widely spaced nipples.
Fig. 7. A 45,X/46,XX patient showing short stature, characteristic facial features, webbed neck, lymphocytic thyroiditis, and follicular formation of thymus medulla.
Fig. 8. An adult patient with 45,X/46,XX mosaic Turner syndrome showing webbed neck with low posterior hair line and short metacarpals, illustrated by hand radiograph.
Fig. 9. A girl with 45,X/46,X,r(X) ring chromosome X Turner mosaicism. The ring chromosome is illustrated by partial karyotype with ideogram and FISH with an X chromosome centromelic probe.
Fig. 10. 45,X karyotype.
Fig.11. FISH showing a mosaic fetus with XXX/X (CEP X/SpectrumOrange). Three copies of the orange signal are in the XXX cells and one copy in the monosomy X cells.
